RESUMO
Leptin is a pleiotropic adipokine that regulates immunometabolism centrally and peripherally. Obese individuals present increased levels of leptin in the blood and develop hypothalamic resistance to this adipokine. Here we investigated whether leptin effects on the periphery are maintained despite the hypothalamic resistance. We previously reported that leptin injection induces in vivo neutrophil migration and peritoneal macrophage activation in lean mice through TNF-α- and CXCL1-dependent mechanisms. However, leptin effects on leukocyte biology during obesity remain unclear. In this study, we investigated the in vivo responsiveness of leukocytes to i.p. injected leptin in mice with diet-induced obesity (DIO). After 14-16 wk, high-sucrose, high-fat diet (HFD)-fed mice showed hyperglycemia, hyperleptinemia, and dyslipidemia compared to normal-sucrose, normal-fat diet (ND). Exogenous leptin did not reduce food intake in DIO mice in contrast to control mice, indicating that DIO mice were centrally resistant to leptin. Regardless of the diet, we found increased levels of TNF-α and CXCL1 in the animals injected with leptin, alongside a pronounced neutrophil migration to the peritoneal cavity and enhanced biogenesis of lipid droplets in peritoneal macrophages. Supporting our in vivo results, data from ex vivo leptin stimulation experiments confirmed hypothalamic resistance in DIO mice, whereas bone marrow cells responded to leptin stimulation through mTOR signaling despite obesity. Altogether, our results show that leukocytes responded equally to leptin in ND- or HFD-fed mice. These results support a role for leptin in the innate immune response also in obesity, contributing to the inflammatory status that leads to the development of metabolic disease.
Assuntos
Imunidade Inata , Leptina/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Leucócitos/imunologia , Leucócitos/metabolismo , CamundongosRESUMO
Lipid droplets (lipid bodies, LDs) are dynamic organelles that have important roles in regulating lipid metabolism, energy homeostasis, cell signaling, membrane trafficking, and inflammation. LD biogenesis, composition, and functions are highly regulated and may vary according to the stimuli, cell type, activation state, and inflammatory environment. Increased cytoplasmic LDs are frequently observed in leukocytes and other cells in a number of infectious diseases. Accumulating evidence reveals LDs participation in fundamental mechanisms of host-pathogen interactions, including cell signaling and immunity. LDs are sources of eicosanoid production, and may participate in different aspects of innate signaling and antigen presentation. In addition, intracellular pathogens evolved mechanisms to subvert host metabolism and may use host LDs, as ways of immune evasion and nutrients source. Here, we review mechanisms of LDs biogenesis and their contributions to the infection progress, and discuss the latest discoveries on mechanisms and pathways involving LDs roles as regulators of the immune response to protozoan infection.
Assuntos
Interações Hospedeiro-Parasita , Gotículas Lipídicas/imunologia , Metabolismo dos Lipídeos , Lipídeos/biossíntese , Biogênese de Organelas , Animais , Apresentação de Antígeno , Homeostase , Interações Hospedeiro-Patógeno , Humanos , Camundongos , Transporte Proteico , Infecções por Protozoários/imunologia , Transdução de Sinais/imunologiaRESUMO
PURPOSE: To determine Toxoplasma gondii genotype in scars of retinochoroiditis in humans. DESIGN: Immunopathology analysis. METHODS: DNA was isolated from retinochoroidal specimens taken from the borders of the scars from eye bank eyes as well as enucleated eyes from uveitis patients with retinochoroidal toxoplasmic scars. The SAG2 region was amplified by polymerase chain reaction and analyzed by restriction fragment length polymorphism. RESULTS: Of the 92 eyes studied, 9 had toxoplasmic scars. All of them, as well as the 2 enucleated eyes, disclosed the presence of type I parasites by the gel electrophoresis analysis of the restriction fragment length polymorphism from SAG2. CONCLUSION: These results suggest that type I strain seems to be responsible for the ocular infections in the population studied.
Assuntos
Coriorretinite/parasitologia , DNA de Protozoário/análise , Genótipo , Toxoplasma/genética , Toxoplasmose Ocular/parasitologia , Animais , Antígenos de Protozoários/genética , Brasil/epidemiologia , Coriorretinite/epidemiologia , Bancos de Olhos , Enucleação Ocular , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Proteínas de Protozoários/genética , Toxoplasmose Ocular/epidemiologiaRESUMO
BACKGROUND AND AIMS: Toxoplasmic retinochoroiditis may recur months or years after the primary infection. Rupture of dormant cysts in the retina is the accepted hypothesis to explain recurrence. Here, the authors present evidence supporting the presence of Toxoplasma gondii in the peripheral blood of immunocompetent patients. METHODS: Direct observation by light microscopy and by immunofluorescence assay was performed, and results were confirmed by PCR amplification of parasite DNA. RESULTS: The authors studied 20 patients from Erechim, Brazil, including acute infected patients, patients with recurrent active toxoplasmic retinochoroiditis, patients with old toxoplasmic retinal scars, and patients with circulating IgG antibodies against T gondii and absence of ocular lesions. Blood samples were analysed, and T gondii was found in the blood of acutely and chronically infected patients regardless of toxoplasmic retinochoroiditis. CONCLUSIONS: The results indicate that the parasite may circulate in the blood of immunocompetent individuals and that parasitaemia could be associated with the reactivation of the ocular disease.
Assuntos
Coriorretinite/parasitologia , Imunocompetência , Toxoplasma/isolamento & purificação , Toxoplasmose Ocular/parasitologia , Adolescente , Adulto , Idoso , Animais , Anticorpos Antiprotozoários/sangue , Brasil , Criança , Coriorretinite/imunologia , DNA de Protozoário/sangue , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Toxoplasma/imunologia , Toxoplasmose Ocular/imunologia , Adulto JovemRESUMO
ASA (acetylsalicylic acid) is an NSAID (non-steroidal anti-inflammatory drug). ASA has gained attention as a potential chemopreventive and chemotherapeutic agent for several neoplasms. The aim of this study was to analyse the possible antitumoural effects of ASA in two erythroleukaemic cell lines, with or without the MDR (multidrug resistance) phenotype. The mechanism of action of different concentrations of ASA were compared in K562 (non-MDR) and Lucena (MDR) cells by analysing cell viability, apoptosis and necrosis, intracellular ROS (reactive oxygen species) formation and bcl-2, p53 and cox-2 gene expression. ASA inhibited the cellular proliferation or induced toxicity in K562 and Lucena cell lines, irrespective of the MDR phenotype. The ASA treatment provoked death by apoptosis and necrosis in K562 cells and only by necrosis in Lucena cells. ASA also showed antioxidant activity in both cell lines. The bcl-2, p53 and cox-2 genes in both cell lines treated with ASA seem to exhibit different patterns of expression. However, normal lymphocytes treated with the same ASA concentrations were more resistant than tumoral cells. The results of this work show that both cell lines responded to treatment with ASA, demonstrating a possible antitumoral and anti-MDR role for this drug.
Assuntos
Antineoplásicos/farmacologia , Aspirina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Apoptose , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Linfócitos/efeitos dos fármacos , Linfócitos/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Infection with Toxoplasma gondii results in retinochoroiditis in 6% to 20% of immunocompetent individuals. The outcome of infection is the result of a set of interactions involving host genetic background, environmental, and social factors, and the genetic background of the parasite, all of which can be further modified by additional infections or even reinfection. Genes that encode several components of the immune system exhibit polymorphisms in their regulatory and coding regions that affect level and type of expression in response to stimuli, directing the immune response into different pathways. These variant alleles have been associated with susceptibility to immune-mediated diseases and with severity of pathology. We have investigated polymorphisms in several of these genes, identified as candidates for progression to retinochoroiditis caused by toxoplasmosis, namely chemokine (C-C motif) receptor 5 (CCR5), toll-like receptor-2 (TLR2), and TLR4. Furthermore, because interleukin-12 (IL-12) has been shown to be fundamental both in mice and in man to control a protective response against T. gondii, molecules that have a key function in IL-12 production will be emphasized in this review, in addition to discussing the importance of the genetic background of the parasite in the establishment of ocular disease.
RESUMO
PURPOSE: Ocular lesions are frequent in various individuals infected with Toxoplasma gondii. Disease intensity in ocular toxoplasmosis varies greatly between patients. Autoimmunity has been suggested as a possible component to retinal destruction. METHODS: Immunologic parameters in the response to retina antigens were evaluated in infected persons with and without ocular lesions and in non-infected controls. Subjects were divided into groups on the basis of titers of serum antibodies to T. gondii, presence and severity of ocular lesions, and clinical history. RESULTS: Peripheral blood mononuclear cells from patients with mild disease responded to one or more retinal antigens with a significantly higher frequency than patients without disease or with severe disease. Interestingly, the cytokines produced by the proliferating mononuclear cells did not follow any specific patterns, except for the fact that IL-4 and IL-5 were seldom detected. CONCLUSIONS: Our results suggest that although the presence of an immune response towards autoantigens is not protective against the development of ocular lesions by the T. gondii, it may protect against the development of severe disease.